Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al. in 1982 (Nature, 296: 659(1982)). NPY is widely distributed in the central nervous system and the peripheral nervous system and plays various roles as one of the most abundant peptide in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the secretion of various hormones or the action of the nervous system. It is known that the continuous intracerebroventricular administration of NPY induces obesity and insulin resistance based on these actions (International Journal of Obesity, vol. 19:517(1995); Endocrinology, vol. 133: 1753(1993)). It is also known that NPY has central effects, such as depression, anxiety, schizophrenia, pain, dementia, or the like (Drugs, vol. 52: 371(1996)). Further, in the periphery, NPY coexists with norepinephrine in sympathetic nerve ending and is involved in the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the effects of other vasoconstrictive substances such as norepinephrine (British Journal of Pharmacology, vol. 95: 419(1988)). It is also reported that NPY is involved in the enhancement of cardiac hypertrophy as a result of the acceleration of sympathetic nervous system (Proceeding National Academic Science USA, vol. 97: 1595(2000)).
Further, it Is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual and reproductive function, gastrointestinal motility, bronchoconstriction, inflammation and alcohol preference (Life Science, vol. 55: 551(1994); The Journal of Allergy and Immunology, vol. 101: S345(1998); Nature, vol. 396: 366(1998)).
NPY has a variety of pharmacological effects which result from its binding to some receptors to which peptide YY and pancreatic polypeptide, which are similar to NPY, also bind. It is known that these pharmacological effects are caused and mediated by the action of, at least, five receptors with or without synergistic interactions (Trends in Neuroscience, vol. 20: 294(1997)).
It is reported that the central action mediated by NPY Y1 receptor includes the remarkable orexigenic effect (Endocrinology, vol. 137: 3177(1996); Endocrinology, vol. 141: 1011(2000)). Further, it is reported that NPY Y1 receptor is involved in anxiety and pain (Nature, vol. 259: 528(1993); Brain research, vol. 859: 361(2000)). In addition, the pressor effects mediated by the strong action of vasoconstriction in the periphery is also reported. (FEBS Letters, vol. 362: 192(1995); Nature Medicine, vol. 4: 722(1998)).
It is known that actions mediated by NPY Y2 receptor include the inhibitory effect on the release of various neurotransmitters in the nerve endings (British Journal of Pharmacology, vol. 102: 41(1991); Synapse, vol. 2: 299(1988)). In the periphery, NPY causes constriction of blood vessel or vas deferens directly or by controlling these neurotransmitters (The Journal of Pharmacology and Experimental Therapeutics, vol. 261:863(1992); British Journal of Pharmacology, vol. 100: 190(1990)). In addition, inhibition of lipolysis in adipose tissues is known (Endocrinology, vol. 131: 1970(1992)). Further, the inhibition of ion secretion in the gastrointestinal tract is reported (British Journal of Pharmacology, vol. 101: 247(1990)).
On the other hand, the effect on the central nervous system functions such as memory and anxiety are also reported (Brain Research, vol. 503: 73(1989); Peptides, vol. 19: 359(1998)).
It is reported that NPY Y3 receptor is expressed mainly in brain stem and in the heart and is related to regulation of blood pressure and heart rate (The Journal of Pharmacology and Experimental Therapeutics, vol. 258: 633(1991); Peptides, vol. 11: 545(1990)). Further, it is known that NPY Y3 receptor is involved in the control of catecholamine secretion in adrenal gland (The Journal of Pharmacology and Experimental Therapeutics, vol. 244: 468(1988); Life Science, vol. 50: PL7 (1992)).
NPY Y4 receptor has a high affinity especially for pancreatic polypeptide and has pharmacological effects on the inhibition of pancreatic exocrine secretion and the gastro-intestinal motility (Gastroenterology, vol. 85: 1411(1983)). Further, it is reported that NPY enhances the secretion of the sexual hormone in the central nervous system (Endocrinology, vol. 140: 5171 (1999)).
The effects mediated by NPY Y5 receptor include the remarkable fat accumulating action including the orexigenic effect (Nature, vol. 382: 168(1996)); American Journal of Physiology, vol. 277: R1428 (1999)). It is reported that the NPY Y5 receptor also mediates the central nervous system effects, such as seizure and epilepsy, or pain and the morphine withdrawal symptoms (Nature Medicine, vol. 3: 761(1997); Proceeding National Academic Science USA, vol. 96: 13518(1999)); The Journal of Pharmacology and Experimental Therapeutics, vol. 284: 633(1998)). It is reported that in the periphery, NPY Y5receptor is involved in diuretic action and hypoglycemic effect (British Journal of Pharmacology, vol. 120: 1335(1998); Endocrinology, vol. 139: 3018(1998)). It is also reported that NPY enhances cardiac hypertrophy as a result of the acceleration of sympathetic nervous system (Proceeding National Academic Science USA, vol. 97: 1595(2000)).
The function of NPY is caused by binding to the NPY receptors existing in the central or peripheral nervous system. Therefore, expression of the effect of NPY can be curbed by blocking the binding of NPY to NPY receptors. Substances which antagonize NPY binding to NPY receptors may be useful for the prophylaxis or treatment of various diseases which NPY relates to, such as cardiovascular disorders exemplified by hypertension, nephropathy, heart diseases and vasospasm, central nervous system disorders exemplified by bulimia, depression, anxiety, convulsion, epilepsy, dementia, pain, alcoholism and drug withdrawal, metabolic diseases exemplified by obesity, diabetes and hormone abnormality, sexual and reproductive dysfunction, gastro-intestinal motility disorder, respiratory disorder, inflammation or glaucoma, or the like (Trends in Pharmacological Science, 15: 153(1994); Life Science, 55: 551(1994); Drugs, vol. 52: 371(1996); The Journal of Allergy and Immunology, vol. 101: S345(1998); Nature, vol. 396: 366(1998); The Journal of Pharmacology and Experimental Therapeutics, vol. 284: 633(1998); Trends in Pharmacological Science, vol. 20: 104(1999); Proceeding National Academic Science USA, vol. 97: 1595(2000)).
Recently, the investigation of the present inventors has revealed that some kind of NPY receptor antagonist is useful in the prophylaxis or treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis (International application publication WO99/27965).
Imidazolone derivatives are disclosed in International application publication WO 99/48888 and these compounds are described to have NPY receptor antagonistic activities. However, the compounds of the present invention are neither disclosed nor suggested.
2,4,4-triphenyl-2-imidazoline is described in CA 52:17240f of Chemical Abstracts, however, NPY receptor antagonistic activities of the compound are neither disclosed nor suggested.